These include: 1) a study of the initial mechanisms of loss of vascular smooth muscle (VSM) tone at the cell and membrane level occurring during prolonged hypotensive stress (e.g., hemorrhagic, endotoxin); 2) application of measuring techniques developed in our laboratory to determine changes in the neural, humoral, and ionic variables underlying such loss; 3) a comparative study of differences in reactivity to circulatory stress of arterial and venous VSM in compensatory (e.g., mesenteric) and non-compensatory (e.g., skeletal and cerebral) vascular beds. Dogs and rats will be subjected to a prolonged period of controlled hypotension induced by hemorrhage and by endotoxin administration. VSM properties and variables affecting VSM tension that will be measured in the hypotensive state both in vivo and in vitro include: (1) VSM membrane potentials and electrical activity; (2) VSM reactivity and sensitivity (via changes in blood vessel diameters and intralumenal pressure) to splanchnic nerve stimulation, suffusion with vasoactive humoral agents (e.g., catecholamines) and blocking agents (e.g., tetrodotoxin, alpha and beta receptor blockers) and ions (e.g., K and Ca 2 ions; (3) endogenous sympathetic efferent activity to VSM; (4) tissue and plasma concentrations of catecholamines, K ions, Ca 2 ions. The data of such measurements should help clarify the relative importance and sequence and mechanism of failure of neurogenic, humoral and related ionic control of VSM tension particularly during severe alterations of the circulatory homeostatic control mechanisms.